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The Role of Dynamic DNA Methylation in Liver Transplant Rejection in Children

Transcriptional regulation of liver transplant (LT) rejection may reveal novel predictive and therapeutic targets. The purpose of this article is to test the role of differential DNA methylation in children with biopsy-proven acute cellular rejection after LT. METHODS. Paired peripheral blood DNA sa...

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Autores principales: Ningappa, Mylarappa, Shao, Xiaojian, Ashokkumar, Chethan, Xu, Qingyong, Zeevi, Adriana, Grundberg, Elin, Pastinen, Tomi, Sindhi, Rakesh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9575761/
https://www.ncbi.nlm.nih.gov/pubmed/36259078
http://dx.doi.org/10.1097/TXD.0000000000001394
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author Ningappa, Mylarappa
Shao, Xiaojian
Ashokkumar, Chethan
Xu, Qingyong
Zeevi, Adriana
Grundberg, Elin
Pastinen, Tomi
Sindhi, Rakesh
author_facet Ningappa, Mylarappa
Shao, Xiaojian
Ashokkumar, Chethan
Xu, Qingyong
Zeevi, Adriana
Grundberg, Elin
Pastinen, Tomi
Sindhi, Rakesh
author_sort Ningappa, Mylarappa
collection PubMed
description Transcriptional regulation of liver transplant (LT) rejection may reveal novel predictive and therapeutic targets. The purpose of this article is to test the role of differential DNA methylation in children with biopsy-proven acute cellular rejection after LT. METHODS. Paired peripheral blood DNA samples were obtained before and after LT from 17 children, including 4 rejectors (Rs) and 13 nonrejectors (NRs), and assayed with MethylC capture sequencing approach covering 5 million CpGs in immune-cell–specific regulatory elements. Differentially methylated CpGs (DMCs) were identified using generalized linear regression models adjusting for sex and age and merged into differentially methylated regions (DMRs) comprising 3 or more DMCs. RESULTS. Contrasting Rs versus NRs, we identified 2238 DMCs in post-LT and 2620 DMCs in pre-LT samples, which clustered in 216 and 282 DMRs, respectively. DMCs associated with R were enriched in enhancers and depleted in promoters. Among DMRs, the proportion of hypomethylated DMRs increased from 61/282 (22%) in pre-LT to 103/216 (48%, P < 0.0001) in post-LT samples. The highest-ranked biological processes enriched in post-LT DMCs were antigen processing and presentation via major histocompatibility complex (MHC) class I, MHC class I complex, and peptide binding (P < 7.92 × 10(−17)), respectively. Top-ranked DMRs mapped to genes that mediate B-cell receptor signaling (ADAP1) or regulate several immune cells (ARRB2) (P < 3.75 × 10(−08)). DMRs in MHC class I genes were enriched for single nucleotide polymorphisms (SNPs), which bind transcription factors, affect gene expression and splicing, or alter peptide-binding amino acid sequences. CONCLUSIONS. Dynamic methylation in distal regulatory regions reveals known transplant-relevant MHC-dependent rejection pathways and identifies novel loci for future mechanistic evaluations in pediatric transplant subcohorts.
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spelling pubmed-95757612022-10-17 The Role of Dynamic DNA Methylation in Liver Transplant Rejection in Children Ningappa, Mylarappa Shao, Xiaojian Ashokkumar, Chethan Xu, Qingyong Zeevi, Adriana Grundberg, Elin Pastinen, Tomi Sindhi, Rakesh Transplant Direct Liver Transplantation Transcriptional regulation of liver transplant (LT) rejection may reveal novel predictive and therapeutic targets. The purpose of this article is to test the role of differential DNA methylation in children with biopsy-proven acute cellular rejection after LT. METHODS. Paired peripheral blood DNA samples were obtained before and after LT from 17 children, including 4 rejectors (Rs) and 13 nonrejectors (NRs), and assayed with MethylC capture sequencing approach covering 5 million CpGs in immune-cell–specific regulatory elements. Differentially methylated CpGs (DMCs) were identified using generalized linear regression models adjusting for sex and age and merged into differentially methylated regions (DMRs) comprising 3 or more DMCs. RESULTS. Contrasting Rs versus NRs, we identified 2238 DMCs in post-LT and 2620 DMCs in pre-LT samples, which clustered in 216 and 282 DMRs, respectively. DMCs associated with R were enriched in enhancers and depleted in promoters. Among DMRs, the proportion of hypomethylated DMRs increased from 61/282 (22%) in pre-LT to 103/216 (48%, P < 0.0001) in post-LT samples. The highest-ranked biological processes enriched in post-LT DMCs were antigen processing and presentation via major histocompatibility complex (MHC) class I, MHC class I complex, and peptide binding (P < 7.92 × 10(−17)), respectively. Top-ranked DMRs mapped to genes that mediate B-cell receptor signaling (ADAP1) or regulate several immune cells (ARRB2) (P < 3.75 × 10(−08)). DMRs in MHC class I genes were enriched for single nucleotide polymorphisms (SNPs), which bind transcription factors, affect gene expression and splicing, or alter peptide-binding amino acid sequences. CONCLUSIONS. Dynamic methylation in distal regulatory regions reveals known transplant-relevant MHC-dependent rejection pathways and identifies novel loci for future mechanistic evaluations in pediatric transplant subcohorts. Lippincott Williams & Wilkins 2022-10-14 /pmc/articles/PMC9575761/ /pubmed/36259078 http://dx.doi.org/10.1097/TXD.0000000000001394 Text en Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Liver Transplantation
Ningappa, Mylarappa
Shao, Xiaojian
Ashokkumar, Chethan
Xu, Qingyong
Zeevi, Adriana
Grundberg, Elin
Pastinen, Tomi
Sindhi, Rakesh
The Role of Dynamic DNA Methylation in Liver Transplant Rejection in Children
title The Role of Dynamic DNA Methylation in Liver Transplant Rejection in Children
title_full The Role of Dynamic DNA Methylation in Liver Transplant Rejection in Children
title_fullStr The Role of Dynamic DNA Methylation in Liver Transplant Rejection in Children
title_full_unstemmed The Role of Dynamic DNA Methylation in Liver Transplant Rejection in Children
title_short The Role of Dynamic DNA Methylation in Liver Transplant Rejection in Children
title_sort role of dynamic dna methylation in liver transplant rejection in children
topic Liver Transplantation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9575761/
https://www.ncbi.nlm.nih.gov/pubmed/36259078
http://dx.doi.org/10.1097/TXD.0000000000001394
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